The present invention relates to novel Carboxamides (CRBAl to CRBA2) synthesized by copper catalyzed Huisgen 1,3-dipolar cycloaddition of alkynes and azides for constructing substituted l,2,3-triazole-4-carboxylate. This l,2,3-triazole-4-carboxylate was converted into substituted l,2,3-triazole-4-caboxamide by successive treatment with hydrazine and phthalic anhydride.
BACKGROUND OF THE INVENTION:
US Publication No. 20120115817 describes preparation of phthalimide derivatives of non-steroidal and/or TNF-a modulating anti-inflammatory compound.
Chan et al (Bioorganic & Medicinal Chemistry, 2008, 16(7), 3626-3631) describes benzothiazole containing phthalimide and their anticancer activity.
US Publication No. 20140155619A1 describe preparation of triazole carboxamides by reacting substituted organic azides with 2-chloroacrylamide.
Click approach or Huisgen 1,3-dipolar cycloaddition to generate 1,2,3-triazoles is described by Sharpless et. al. in Angew Chem Int Ed Engl. 2001, 40(11), 2004-2021.
Brse, S., & Banert, K. (Eds.). (2009). Organic Azides. John Wiley & Sons, Ltd. https://doi.org/10.1002/9780470682517 describes various methods to prepare organic azides.
However, nowhere in the background art the novel series of carboxamides containing 1,2,3-triazole and their phthalamide derivatives are disclosed or suggested.
SUMMARY OF THE INVENTION
The present invention provides a novel process for the preparation Substituted N-(l,3-dioxoisoindolin-2-yl)-l-phenyl-7//-l,2,3-triazole-4-carboxamide with three steps described.
The process also improves overall reaction yields and is more consistent and reproducible. Furthermore, the reaction mixture work-up and the final product recovery require fewer steps, thus affording the final product in short times, higher yields and higher purity. Column purification is rarely required. Different crystallization techniques give pure product in highest yield.
The invention relates to the preparation of l,2,3-triazole-4-carboxamide of general Formula I:
O

R-i Formula I
wherein Ri may be selected from hydrogen, alkyl, alkyl halides, substituted phenyl ring with H, F, CI, Br, N02, I, CH3, OR, C(0)R, COOH, COOR, SH, SR or heterocyclic ring like pyrazole,

benzimidazole, imidazole, thiazole, azoles etc. Ri can be a linear or branched alkyl group, for example a C1-C5 alkyl group. The alkyl group may contain unsaturation unit such as double bond (eg. C=C, C=N, C=0, C=S etc.) or triple bond (Alkynyl, Azido, Cyano etc) in addition to other substitutions. R2 describes substitution in phthalamide ring such as H, F, CI, Br, NO2, I, CH3, OR, C(0)R, or heterocyclic ring. R2 can also be chosen from fused/bridged carbocyclic or heterocyclic saturated or unsaturated ring residue. In exemplary embodiments, Ri is independently selected from phenyl ring substituted with H, F, CI, Br, NO2, CH3 and I.
In exemplary embodiments, the invention relates to the preparation /V-(l,3-dioxoisoindolin-2-yl)-l-(3-nitrophenyl)-7//-l,2,3-triazole-4-carboxamide of Formula II in which Ri Formula I are m-N02-C6H4.


Formula II

In a preliminary step, a substituted aniline of general Formula III is converted into a substituted azido benzene of general Formula IV by following the procedure Substituted aniline (1 equivalent, 5 mmol) was dissolved in aq. HC1 solution (50 mL) at room temperature stir for 10 min. NaN02 (1 eq, 5 mmol) was added in the reaction mixture upon cooling 0°C, stirred for 30 min at 0-5 °C. Added sodium acetate and then add Sodium azide (1.2 eq, 6 mmol) to the mixture stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc. The organic layer was washed with water, brine, dried over Na2S04, and evaporated under reduced pressure to give pure substituted azide enough for further reactions.
NH

Formula III Formula IV
Where in R4 may be selected from H, F, CI, Br, NO2,1, CH3, OR, C(0)R,, COOH, COOR, SH, SR or heterocyclic ring like pyrazole, benzimidazole, imidazole, thiazole, azoles etc. Formula IV can be written in its general form as Formula IVA. Synthesis of general formula IVA can be carried out by using common methods (Brse, S., & Banert, K. (Eds.). (2009). Organic Azides. John Wiley & Sons, Ltd. https://doi.org/10.1002/9780470682517) apparent to persons skilled in the art.
R1-N3
Formula IVA
The substituted azidobenzene of general Formula IV is then reacted with alkyl propiolate of Formula V (where R3 could be methyl, ethyl, n-propyl, iso-propyl, or any alkyl group) to directly obtain l,2,3-triazole-4-carboxamide of general Formula VI, where in R3 can be selected from Me, Ethyl, or any alkyl group, aryl group, heterocycle.

R4 +

N,
Formula IV

O
OR,
Formula V

Formula VI

Refluxing the l,2,3-triazole-4-carboxylate of general Formula VI with hydrazine hydrate using common methods apparent to persons skilled in the art gives Formula VII.



OR,
NHNH,
Formula VI

The l,2,3-triazole-4-carbhydrazide of general formula VII directly give l,2,3-triazole-4-carboxamide structure of Formula I by heating with phthalic anhydride or substituted phthalic anhydride.



NHNH,

In one exemplary embodiment, the present invention provides a process as well as preparation for the novel of l,2,3-triazole-4-carboxamide belong to the structure of Formula II

0,N ?
XT-.
-N Formula II
by the steps of
(a) reacting w-Nitro aniline with sodium azide to obtain substituted l-azido-3-nitrobenzene;


XX

(b) reacting substituted l-azido-3-nitrobenzene with Ethyl propiolate to form ethyl l-(3-nitrophenyl)-777-l,2,3-triazole-4-carboxylate;
EtO N=N

1 ^ //VNv/^.N02
O

c) refluxing ethyl l-(3-nitrophenyl)-777-l,2,3-triazole-4-carboxylate with hydrazin hydrate to
obtain l-(3-nitrophenyl)-777-l,2,3-triazole-4-carbohydrazide
EtO N=N H2NHN NcrN
0 XX ° X7
d) heating l-(3-nitrophenyl)-777-l,2,3-triazole-4-carbohydrazide with phthalic anhydride to
obtain jV-(l,3-dioxoisoindolin-2-yl)-l-(3-nitrophenyl)-777-l,2,3-triazole-4-carboxamide



NO,
O TT ^T W>^( /r^.N. /^/NO:
H2NHN N=N

Formula II
Isolating the obtained jV-(l,3-dioxoisoindolin-2-yl)-l-(3-nitrophenyl)-777-l,2,3-triazole-4-carboxamide
OBJECTIVE OF INVENTION
Objectives of invention includes the novel methods to synthesize molecule of structure Formula I and Formula VIII.
BRIEF DESCRIPTION OF THE DRAWINGS, IF ANY
For a full understanding of the present invention, reference should now be made to the following detailed description of the preferred embodiments of the invention as illustrated in the accompanying drawing and examples. FIG. 1 is schematic overview of synthetic steps involved in the synthesis of Substituted N-(l,3-dioxoisoindolin-2-yl)-l-phenyl-777-l,2,3-triazole-4-carboxamide. FIG. 2 is schematic representation of general methodology to synthesize general Formula I.
DESCRIPTION OF METHOD
For a full understanding of the present invention, reference should now be made to the following detailed description of the preferred embodiments of the invention as illustrated in the accompanying drawing and examples. FIG. 1 is schematic overview of synthetic steps involved in the synthesis of Substituted jV-(l,3-dioxoisoindolin-2-yl)-l-phenyl-777-l,2,3-triazole-4-carboxamide.
Drawings, Figures


NH,
(ii)

->-

Step(i) Step(ii) Step (iii) Step (iv)
FIG. 1: Overview of the synthesis of novel Substituted JV-(1,3-dioxoisoindolin-2-yl)-1-phenyl-7#-1,2,3-triazole-4-carboxamide Reagents and reaction conditions: Reaction conditions: (i) HCl: H2O (1:1), NaNO2 in 15 ml water, CH3COONa, NaN3 in 15 ml water, stir at 0°C to-5°C. (ii) tBuOH:H2O (1:1), Copper acetate, sodium ascorbate and Alkyl propiolate, stirring at room temperature. (iii) Hydrazine hydrate, ethanol, reflux. (iv) Phthalic anhydride and toluene, reflux



N3 (ii) N_ 3> (iii) N„ > ^ r=< H )r^\^~R:
l N
1 1 1 R^N- '-N
Formula IVA Formula VIA Formula VILA

Fig. 2 General methodology to prepare general Formula I, phthalamide derivative of 1,2,3-triazole-4-carboxamide. Reagent and conditions: (ii) tBuOH:H2O (1:1), Copper acetate, sodium ascorbate and Alkyl propiolate, stirring at room temperature. (iii) Hydrazine hydrate, ethanol, reflux. (iv) Phthalic anhydride and toluene, reflux.
DETAILED DESCRIPTION OF THE INVENTION
The embodiments of the present invention will be described in detail with reference to the accompanying drawing and examples. However, the present invention is not limited to the embodiments. The present invention can be modified in various forms. The embodiments of the present invention are only provided to explain more clearly the present invention to the ordinarily skilled in the art of the present invention and therefore, should not be construed to limit the scope of the invention.
According to a preferred embodiment of the present invention synthetic carboxamide comprises a 1,2,3-triazole moiety which is linked with N-1 position with substituted benzene, aromatic or heterocyclic ring wherein other side of triazole ring bound with amide linkage with phthalamide formula I, were R1 is an alkyl, aryl or heterocyclic ring system. Alkyl group could be one of the unsubstituted or substituted aliphatic hydrocarbon chain. Aryl group could be one of the unsubstituted or substituted aromatic hydrocarbon such as benzene etc. Heterocyclic group could be one of the unsubstituted or substituted heterocyclic ring such as pyridine, imidazole, benzimidazole, pyrrol, furan, triazole, azole or any heterocyclic system. R can be a linear or branched alkyl group, for example a C1-C5 alkyl group. The alkyl group may contain unsaturation unit such as double bond (eg. C=C, C=N, C=O, C=S etc.) or triple bond (Alkynyl,
6

Azido, Cyano etc) in addition to other substitutions. R2 describes substitution in phthalamide ring such as H, F, Cl, Br, NO2, I, CH3, OR, C(O)R, or heterocyclic ring. R2 can also be chosen from fused/bridged carbocyclic or heterocyclic saturated or unsaturated ring residue. In exemplary embodiments, R is independently selected from phenyl ring substituted with H, F, Cl, Br, NO2, CH3 and I.


Ri Formula I
Substituted 1,2,3-triazole-4-carboxylate synthesis
To a 250 mL conical flask were added degassed (with argon) tBuOH:H2O (1:1), Substituted azide (13.6 mmol), copper acetate or copper sulphate (0.1 mmol), sodium ascorbate(0.2 mmol) and Ethyl propiolate (12.36 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was bubbled with clean Argon gas through out the course of reaction. Upon reaction completion based on TLC analysis, the mixture was diluted with water and added ammonium hydroxide. The mixture was stir at room temperature for 30 min and extracted with ethyl acetate. The mixture was washed with brine and dried under vacuum in rotatory evaporator to afford compound as amorphous solid.
CRBL1
OEt
02N v N \,
N=N' O
Yellow color solid (1.28 g, 80%); mp 112 °C; FTIR (thin film, cm-1) 1697, 1515, 1337, 1250;
1H NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 8.90 (t, 1H, J=2 Hz), 8.48-8.46 (m, 1H), 8.35-8.33
(m, 1H,), 7.87 (t,1H, J=8.2 Hz), 4.42 (q, 2H, J=7.12 Hz), 1.42 (t, 3H, J=7.12 Hz); 13C NMR
(100 MHz, CDCl3) δ 159.7, 148.4, 140.1, 136.7, 131.3, 127.4, 126.2, 123.4, 115.1, 60.7, 14.1.


CRBL2
02N

N^>

OEt

Yellow color solid (1.9 g, 72%); mp 168 °C; FTIR (thin film, cm-1) 1695, 1505, 1338, 1256; 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.46-8.42 (m, 2H), 8.35-8.31 (m, 2H) 4.42(q, 2H, J=7.08Hz), 1.41 (t, 3H, J=7.12Hz); 13C NMR (100 MHz, DMSO-d6) δ 159.7, 146.9, 140.3,
7

140.3, 127.1, 125.1, 120.8, 60.7, 14.03.
Substituted 1,2,3-triazole-4-carbhydrazide synthesis
To a round bottom flask was added Ethyl 1-(m-nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (3.7mmol), hydrazine hydrate (74 mmol) and ethanol (10.0 mL). The mixture was reflux at 80 °C and monitored by TLC. Upon reaction completion based on TLC analysis, the mixture was cooled to room temperature and ice cold water was added. The mixture was stirred for 15 min and the solids were filtered, washed with petroleum ether and dried to afford the desired 1-(3-nitrophenyl)-1H-1,2,3-triazole-4-carbohydrazide as white color amorphous solid.
CRBH1

HN-NH2 0,N' ^-" "NT
N=N' O
White color solid (344mg, 75%); mp 184 °C; FTIR (thin film, cm"1) 3412, 3337, 3097,1661, 1520, 1351, 1480, 1271; 1H NMR (400 MHz, DMSO-d6) 5 9.91 (bs,1H), 9.50 (s,1H), 8.81 (s,1H) ,8.46-8.44 (m,1H), 8.35-8.33 (m,1H), 7.90 (t, 1H J=8.2 Hz), 4.53 (bs, 2H); 13C NMR (100MHz, DMSO-d6) 5 158.5, 148.3, 142.9, 136.8, 131.2, 125.9, 124.5, 123.1, 114.9.
CRBH2
N-/ O White color solid (386 mg, 84%); mp 262 °C Decomposed; FTIR (thin film, cm"1) 3339, 3103, 1663, 1577, 1346, 1503, 1280; 1H NMR (400 MHz, DMSO-d6) 5 9.90 (bs,1H), 9.47 (s,1H), 8.46-8.42 (m,2H), 8.33-8.28 (m,2H), 4.50 (bs, 2H); 13C NMR (100 MHz, DMSO-d6) 5 120.7, 124.6, 125.2, 140.5, 143.1, 146.8.
Example 1: Substituted 1,2,3-triazole-4-carboxamide Synthesis (CRBA1, CRBA2) and Purification.
The 1,2,3-triazole-4-carboxamide of the present invention may be synthesized by reaction of Substituted 1,2,3-triazole-4-carbohydrazide (100 mg, .4 mmol), Phthalic anhydride (65 mg, 1.1 equiv.) and toluene (20.0 ml) in catalytic amount of glacial acetic acid. The mixture was heated to reflux and monitored by TLC. Upon reaction completion based on TLC analysis, the mixture was cooled to room temperature. The mixture was stirred for 15 min and the solids were filtered, washed with and petroleum ether and dried to afford compound as a white solid.
8

Table 1: Substitution, yield of synthesized Compounds

S.No Substituted ester Yield (%) Substituted hydrazide Yield Substituted carboxamide Yield (%)
1 OT-NO2 80 OT-NO2 75 OT-NO2 72
2 P-NO2 72 P-NO2 84 P-NO2 70
CRBA1

0,N
o o

White color solid (77 mg, 72%); mp 298 °C FTIR (thin film, cm"1) 3265, 3150 1698, 1560,
1330;1510,1250
*H NMR (400 MHz, DMSO-de) 5 11.51 (s, IH), 9.77 (s, 1H),8.89 (t, IH J=1.88), 8.51 (d, IH
J=1.32), 8.38(d, IH J=1.72), 8.08-7.91 (m, 5H); 13C NMR (100 MHz, DMSO-de) 5 167.6,
167.5, 158.2, 143.8, 141.5, 135.8, 134.2, 131.3, 131.2, 130.8, 130.3, 129.2, 128.9, 128.2, 128.1,
127.7, 125.4.

CRBA2
°2NV^ l) ^
c ■\.T^ HN-N N N O O

White color solid (100 mg, 70%); mp 260 °C Decomposed; FTIR (thin film, cm4) 3268, 3146 1701, 1579, 1344, 1517,1262; lU NMR (400 MHz, DMSO-de) 5 11.52 (s, IH), 9.74 (s, IH), 8.92 (t, IH J=2.04), 8.52-8.49 (m, IH), 8.38-8.35 (m, IH), 7.98-7.89 (m, 5H); 13C NMR (100 MHz, DMSO-de) 5 164.7, 158.2, 148.4, 141.2, 136.8, 134.85, 131.2, 129.5, 126.5, 126.2, 123.5, 123.4, 115.2.

WE CLAIM

A process for the preparation as well as novel compounds l,2,3-triazole-4-carboxamide of formula I

Formula I
wherein Ri may be selected from hydrogen, alkyl, alkyl halides, substituted phenyl ring with H, F, CI, Br, N02,1, CH3, OR, C(0)R, COOH, COOR, SH, SR or heterocyclic ring like pyrazole, benzimidazole, imidazole, thiazole, azoles etc. Ri can be a linear or branched alkyl group, for example a C1-C5 alkyl group. The alkyl group may contain unsaturation unit such as double bond (eg. C=C, C=N, C=0, C=S etc.) or triple bond (Alkynyl, Azido, Cyano etc) in addition to other substitutions. R2 describes substitution in phthalamide ring such as H, F, CI, Br, NO2, I, CH3, OR, C(0)R, or heterocyclic ring. R2 can also be chosen from fused/bridged carbocyclic or heterocyclic saturated or unsaturated ring residue.
In exemplary embodiments, Ri is independently selected from phenyl ring substituted with H, F, CI, Br, NO2, CH3 and I.
comprising:
Step- (i)
Reacting Substituted aniline with sodium azide to obtain substituted azidobenzene, wherein R4 is defined as H, F, CI, Br, NO2,1, CH3, OR, C(0)R, or heterocyclic ring like Pyrazole, Benzimidazole, imidazole, thiazole etc.;
NH2 N3
Formula III Formula IV
Step (ii):
reacting substituted l-azido-3-nitrobenzene with Ethyl propiolate to form ethyl l-(3-

nitrophenyl)-li7-l,2,3-triazole-4-carboxylate; where in R3 can be selected from Me, Ethyl, or any alkyl group, aryl group, heterocycle


OR,
R*

R
N,
4 +
Formula IV

O
OR,
Formula V

O
N w
N N
-► N

Formula VI

Step (iii)
Refluxing ethyl l-(3-nitrophenyl)-/i7-l,2,3-triazole-4-carboxylate with hydrazine hydrate to obtain l-(3-nitrophenyl)-7//-l,2,3-triazole-4-carbohydrazide Formula VII.

OR,
NHNH,
R4
R,

N \\ '-> V
o
N

N

N \\ '-' V
O
N

N

Formula VI

Formula VII

Step (iv)
The l,2,3-triazole-4-carbhydrazide of general formula VII directly give l,2,3-triazole-4-carboxamide structure of Formula I by heating with phthalic anhydride or modified phthalic anhydride.



O
NHNH,
N \N
N
-R4 Formula VII

2. The process according to claim 1, wherein Ri is w-nitro-CeFU, azide is an alkali metal azide such as sodium azide or potassium azide.
3. The process according to claim 1, wherein reaction step (ii) is carried out in the

presence of a tertiary butanol:H20 (1:1) at room temperature in the presence of copper acetate, or copper sulphate and sodium ascorbate with argon gas bubbled during the reaction.
4. The process according to claim 1, wherein reaction step (iii) is carried out in the presence of an alcohol having boiling point of at least about 60° C and hydrazine hydrate.
5. The process according to claim 1, wherein reaction step (iv) is conducted in the presence of a acid glacial acetic acid or hydrochloric acid (catalytic amount) and benzene, toluene, xylene or any aromatic hydrocarbon liquid.
6. The process according to claim 5, wherein reaction step (iv) is conducted in the presence of phthalic anhydride or modified phthalic anhydride.
7. The process according to claim 1, 3, 4 and 5 for the synthesis of Formula VII and Formula VIIA.